Mapping the Theories of Preeclampsia and the Role of Angiogenic Factors

Article (PDF Available)inObstetrics and Gynecology 109(1):168-80 · February 2007with165 Reads
DOI: 10.1097/01.AOG.0000249609.04831.7c · Source: PubMed
Abstract
To evaluate claims that elevated soluble fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased placental growth factor predict preeclampsia. MEDLINE (1966-March 2006), EMBASE (1980-June 2006), POPLINE (1980-June 2006), CINAHL (1982-June 2006), and LILACS (1982-June 2006) were searched, and experts contacted. Studies identified and included were those reporting blood and urine levels of sFlt-1 or placental growth factor obtained before gestational week 30 or overt preeclampsia. Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing placental growth factor were included in this review. There was considerable interreport heterogeneity in methodology and results for sFlt-1 measured before gestational week 25. After week 25 placental growth factor and sFlt-1 levels varied consistently between the normal pregnancy group and women destined to develop preeclampsia, achieving significance in women who developed severe preeclampsia. Third-trimester increases in sFlt-1 and decreases in placental growth factor levels are associated with preeclampsia, specifically severe disease, based on retrospective data. The evidence is insufficient to recommend these markers to be used for screening, and prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests.

Figures

Review
Mapping the Theories of Preeclampsia and
the Role of Angiogenic Factors
A Systematic Review
Mariana Widmer,
MSc
, José Villar,
MD
, Ariela Benigni,
PhD
, Agustin Conde-Agudelo,
MD
,
S. Ananth Karumanchi,
MD
, and Marshall Lindheimer,
MD
OBJECTIVE: To evaluate claims that elevated soluble
fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased
placental growth factor predict preeclampsia.
DATA SOURCES: MEDLINE (1966–March 2006), EMBASE
(1980–June 2006), POPLINE (1980 –June 2006), CINAHL
(1982–June 2006), and LILACS (1982–June 2006) were
searched, and experts contacted.
METHODS OF STUDY SELECTION: Studies identified
and included were those reporting blood and urine levels
of sFlt-1 or placental growth factor obtained before
gestational week 30 or overt preeclampsia.
TABULATION, INTEGRATION, AND RESULTS: Ten of
184 available studies analyzing sFlt-1 and 14 of 319
studies analyzing placental growth factor were included
in this review. There was considerable interreport heter-
ogeneity in methodology and results for sFlt-1 measured
before gestational week 25. After week 25 placental
growth factor and sFlt-1 levels varied consistently be-
tween the normal pregnancy group and women destined
to develop preeclampsia, achieving significance in
women who developed severe preeclampsia.
CONCLUSION: Third-trimester increases in sFlt-1 and
decreases in placental growth factor levels are associated
with preeclampsia, specifically severe disease, based on
retrospective data. The evidence is insufficient to recom-
mend these markers to be used for screening, and
prospective studies employing rigorous laboratory and
study design criteria are needed to determine the clinical
usefulness of these tests.
(Obstet Gynecol 2007;109:168–80)
P
reeclampsia, complicating 5–7% of all nulliparous
pregnancies, and its life threatening manifesta-
tions make it a major cause of maternal and perinatal
morbidity and mortality worldwide.
1,2
Thus, there is a
critical need for strategies to predict, prevent, and
improve management of this disorder. Unfortunately,
as of 2006, and due mainly to limited knowledge of
pathogenesis, there were no clinically useful tests to
predict preeclampsia.
3
Recently, investigators have
begun to examine soluble fms-like tyrosine kinase-1
receptors (sFlt-1) and placental growth factor, as early
markers for preeclampsia. We therefore conducted
this systematic review to assess the evidence of the
association between such markers and preeclampsia
and their potential usefulness as early markers of the
condition. Such reviews are also World Health Orga-
nization requirements for any new research
protocols.
4
There are numerous theories concerning cause
From the United Nations Development Programme, United Nations Population
Fund, World Health Organization, World Bank Special Programme of Re-
search, Development and Research Training in Human Reproduction, and
Department of Reproductive Health and Research, World Health Organization,
Geneva, Switzerland; Nuffield Department of Obstetrics and Gynaecology,
University of Oxford, Oxford, United Kingdom; Mario Negri Institute for
Pharmacological Research, Bergamo, Italy; Centro de Estudios e Investigación en
Salud, Department of Obstetrics and Gynecology, Fundación Santa de
Bogota, Bogota, Colombia; Department of Obstetrics and Gynecology, Beth
Israel Deaconess Medical Center and Harvard Medical School, Boston, Massa-
chusetts; and Department of Obstetrics and Gynecology and Medicine, the
University of Chicago, Chicago, Illinois.
Supported by the United Nations Development Programme, United Nations
Population Fund, World Health Organization, World Bank Special Program of
Research, Development and Research Training in Human Reproduction, and
Department of Reproductive Health and Research, World Health Organization,
Geneva, Switzerland.
The views expressed here are solely the responsibility of the authors and do not
necessarily represent the views of the World Health Organization or its member
States.
Corresponding author: Dr. José Villar, Nuffield Department of Obstetrics and
Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, OX39DU,
United Kingdom; e-mail: Jose.Villar@obs-gyn.ox.ac.uk.
Financial Disclosure:
Dr. Karumanchi is listed as a coinventor on multiple patents that have been filed
by the Beth Israel Deaconess Medical Center for the diagnosis and therapy of
preeclampsia. He is also a consultant to Abbott, Beckman Coulter, and Johnson
& Johnson.
© 2006 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/06
168 VOL. 109, NO. 1, JANUARY 2007 OBSTETRICS & GYNECOLOGY
and pathophysiology of preeclampsia, including fail-
ure of trophoblast cell invasion, oxidative stress,
endothelial dysfunction, aberrations in calciotrophic
hormones, and most recently, antiangiogenic pro-
teins.
5
Placentation involves angiogenesis and vascu-
logenesis and ligand and receptor systems, critical to
this process, include vascular endothelial growth fac-
tor (VEGF), placental growth factor, VEGF receptors
(Flt-1), and sFlt-1.
6,7
Flt-1 and sFlt-1 bind VEGF and
placental growth factor. The interaction Flt-1 with
VEGF and placental growth factor activates placental
angiogenesis and vasculogenesis, whereas those be-
tween sFlt-1 and VEGF and placental growth factor
inactivate these proteins, preventing them from bind-
ing to cell-surface receptors, and leading to a state of
angiogenic imbalance and endothelial dysfunction.
6,7
Increased circulating levels of sFlt-1 in preeclampsia
are associated with decreased circulating levels of
VEGF and placental growth factor. Sera from women
with preeclampsia is associated with endothelial dys-
function in vitro that could be reversed by the addi-
tion of angiogenic factors, and increasing sFlt-1 levels
in pregnant rats was shown to produce a preeclamp-
sia-like syndrome in one study.
8,9
All this evidence
implies a possible role for angiogenic and antiangio-
genic proteins in the pathogenesis of preeclampsia.
10
SOURCES
An electronic search strategy was designed to identify
citations that evaluated associations between sFlt-1
and placental growth factor levels and preeclampsia
in MEDLINE (1966 through March 2006), EMBASE
(1980 through June 2006), POPLINE (1980 through
June 2006), CINAHL (1982 through June 2006), and
LILACS (1982 through June 2006) using a combina-
tion of MeSH or key words for angiogenic factors and
preeclampsia, including soluble fms-like tyrosine ki-
nase 1, sFlt-1, soluble vascular endothelial growth
factor receptor-1, VEGF receptor 1, angiogenic fac-
tors, antiangiogenic proteins, angiogenesis, placental
growth factor, PlGF. Terms for preeclampsia included
preeclampsia, eclampsia, gestosis, early pregnancy
hypertension, pregnancy toxemia, pregnancy-in-
duced hypertension, hypertensive disorders of preg-
nancy, gestational hypertension, pregnancy-associ-
ated hypertension, pregnancy hypertension. For
studies with multiple publications, the report includ-
ing the largest sample size was used and supple-
mented if additional information appeared in the
others. If a study evaluated several angiogenic factors,
each was considered independently. Authors were
also contacted to obtain additional data.
STUDY SELECTION
Only studies of blood or urinary placental growth
factor or sFlt-1 levels measured in picograms per
milliliter pregnant populations starting before gesta-
tional week 30 and before diagnosis of preeclampsia
were included. Appropriate definitions of the terms
preeclampsia, severe preeclampsia, and the control
group, as well as notation of the laboratory test used
were additional requirements. Reviews, editorials,
author correspondence, studies of umbilical cord se-
rum or placenta, or reports without extractable data
were excluded. For missing data we attempted to
contact the authors, and if unsuccessful, estimated
values from figures. We extracted data on age, parity,
gestational age at testing, sample size, handling of the
sample, biochemical test, description of the method
and definition of preeclampsia as reported by authors
in the publications.
A formal meta-analysis was deemed inappropri-
ate because of the differences in the methodologies
used and gestational ages at sampling as well as the
heterogeneity of study design and results. Results are
presented as mean (standard deviation) for each
group and study. When expressed as multiple of
medians, we did not transform to actual values. We
calculated the difference between means in pre-
eclamptic and control groups to be presented in bar
figures for descriptive purpose only. We were only
able to calculate likelihood ratio for a few studies
providing sensitivity and specificity. Standard criteria
for evaluation of screening tests are detailed in
Conde-Agudelo et al.
3
Likelihood ratios for a positive
test result above 10 and likelihood ratios for a nega-
tive test result below 0.1 were considered as convinc-
ing positive and negative evidence for prediction. A
coauthor (A.B.) independently evaluated the labora-
tory methodologies following a set of standard criteria
for laboratory procedures agreed upon before review-
ing the reports.
RESULTS
Figure 1 summarizes the search and study inclusion
process for sFlt-1 and placental growth factor. Tables
1 and 2 present the characteristics of the included
studies.
There are 10 of 184 studies
11–20
with sFlt-1 levels
measured retrospectively at different gestational peri-
ods comparing results between women destined to
develop preeclampsia (preeclamptic group) and con-
trol women (Table 3). Soluble fms-like tyrosine ki-
nase-1 was measured in samples stored over various
time periods in all these studies. Only four had data
VOL. 109, NO. 1, JANUARY 2007 Widmer et al Mapping the Theories of Preeclampsia 169
for sensitivity and specificity calculations
11–13,19
and
two permitting calculations of likelihood ratios.
11–12
Results are stratified by gestational age at which
sampling was performed (Table 3).
Soluble fms-like tyrosine kinase-1 levels were
available for blood sampled before gestational week
15 in seven studies.
11,13,14,16–19
(Fig. 2A). No statistically
significant differences were detected between pre-
eclamptic and control groups. In one,
16
levels appear
decreased in the preeclamptic group, whereas these
values tend to increase in the other studies
11,13,14,17–19
(Fig. 2B).
There were eight reports of women studied dur-
ing the 15-25 weeks gestational window.
11,13–17,19,20
Three
15,16,19
showed statistically significantly greater
sFlt-1 levels in the preeclamptic group, although in
one,
15
significance was achieved only in women
whose preeclampsia was classified as “severe” (Fig.
3A). Ironically there was one study
17
with contrary
results, that is, sFlt-1 levels were lower in the pre-
eclamptic group. However, the differences were not
statistically significant (Fig. 3B).
There were five reports of women studied after
gestational week 25,
11–14,17
with multiple sampling in
four
11,13,14,17
(Fig. 4A). Soluble fms-like tyrosine ki-
nase-1 levels were elevated in the preeclamptic
groups in all five reports, including 11 comparisons
(Fig. 4B). Preeclamptics were grouped without distinc-
tion of severity in three reports,
11,12,14
and in each,
sFlt-1 levels were statistically significantly higher in
preeclamptics. In one, however, sFlt-1 levels ap-
proached statistical significance at 37 weeks and were
statistically significantly elevated in the preeclamptic
group at 30 weeks and immediately before delivery.
14
There were two studies that differentiated be-
tween mild and severe preeclampsia.
13,17
In one,
13
significance was observed between weeks 21 and 32
in the severe preeclamptic group only, becoming
Fig. 1. Study selection process:
systematic review of soluble fms-
like tyrosine kinase-1 receptor,
placental growth factor, and pre-
eclampsia. sFlt-1, soluble fms-like
tyrosine kinase-1; PlGF, placental
growth factor.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
170 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
Table 1. Studies Analyzing Soluble fms-Like Tyrosine Kinase-1 Receptor as a Predictor of Preeclampsia
Study
(Location/Language
of Publication)
Sample Size
(Preeclamptics/
Controls)
Preeclamptics:
Mean Maternal Age
[y (SD)]/Nulliparity
[n (%)]
Controls:
Mean Maternal Age
[y (SD)]/Nulliparity
[n (%)]
Blood Sample
(Anticoagulant)/
Storage
Temperature(°C)
Gestational
Age at Sampling
(wk)
Control Group
[Mean (SD)
pg/mL]
Preeclamptic
Group
[Mean (SD)
pg/mL]
Parra
16
2005 (Chile/English) 33/137 29.8 (1.1)/17 (51.5) 30.6 (0.6)/37 (27) Plasma (citrate, EDTA)/84°C 11–14 546.2 (45.1) 379.6 (80.5); P.05
22–25 210 620; P.05
Powers
17
2005 (US/English) 55/113 Mild PE 24.6 (1.0);
severe PE 27.8 (1.6)/47
(85)
25.7 (0.5)/95 (84) Serum/70°C Less than 6 30-40 Similar to control
10–14.9 890 (58) Similar to control
15–24.9 906.77 (1,289.59) Mild PE: 825.23
(518.14)sPE: 522.85
(202.58)
25–34.9 726.17 (507.77) Mild PE: 787.27
(1,170.41)sPE: 1,011.95
(1,966.92); P.05
35-delivery 2,175.52 (1,184.80) Mild PE: 3,053.21
(1,755); P0.05
sPE: 4,010.86
(4,511.54); P0.05
48 h postpartum 900 Mild PE: 1,200; P.005
sPE: 3,400; P.005
Thadani
18
2004 (US/English) 40/80 31 (6)/not stated 30 (6)/not stated Serum/80°C First trimester 973 (490) 1,048 (657)
Park
15
2005 (Korea/English) 32/128 34.3 (4.7)/21(66) 33.5 (4.4)/84 (66) Plasma (EDTA)/70°C Mid trimester 531 (371) Mild PE: 750 (908)sPE:
962 (688); P.001
PE: 869 (785); P.05
McKeeman
14
2004
(UK/English)
14/33 Not stated/not stated Not stated/not stated Serum/70°C 12 430 (30) 570 (70)
20 390 (40) 550 (110)
30 500 (30) 1,270 (380); P.012
37 950 (80) 1,670 (360)
24 h before delivery 1,583 2,670; P .001
24 h after delivery 610 720
Chaiworapongsa
11
2005 (US/
English)
44/44 26 (6)/30 (68.2) 29 (6)/11(25) Plasma (EDTA)/70°C 7–16 464 (260) 546 (271)
16.1–24 560 (351) 585 (369)
24.1–28 708 (426) 931 (436); P.02
28.1–32 823 (376) 1,621 (1,212); P.001
32.1–37 1,183 (482) 2,585 (1,172); P.001
More than 37 2,193 (1,374) 4,995 (3,145); P.001
Levine
13
2004 (US/English) 120/120 20.8 (4.5)/97 (80.8) 20.2 (3.6)/95 (79.2) Serum/70°C 13–16 950 950
17–20 800 850
21–32 876 Mild PE: 985sPE: 1,200;
P.02
33–41 1,796 Mild PE: 2,442; P.001
sPE: 3,000; P.001
Hertig
12
2004 (France/English) 8/9 Not stated/not stated Not stated/not stated Serum/20°C Less than 20 No significant difference
25–28 552 (246) 2,779 (1,837); P.028
At delivery 1,483 (1148) 5,332 (3,187); P.027
Wathe´n
19
2006
(Finland/English)
49/59 32 (5)/23 (46.9) 32 (5)/16 (27.1) Serum/80°C 12–15 432 Mild PE: 463sPE: 489
16–20 296 Mild PE: 340; P.043
sPE: 497; P.022
Savvidou
20
2006 (UK/English) 13/42 28/10 (77) 30/23 (55) Serum 23–25 463 690.5
SD, standard deviation; EDTA, ethylenediaminetetraacetic acid; PE, preeclampsia; Mild PE, mild preeclampsia; sPE, severe preeclampsia.
P values are from the comparison between preeclamptic and control groups.
VOL. 109, NO. 1, JANUARY 2007 Widmer et al Mapping the Theories of Preeclampsia 171
Table 2. Studies Analyzing Placental Growth Factor as Predictor of Preeclampsia
Study
(Location/Language
of Publication)
Sample
Size(Cases/
Controls)
Cases: Mean
Maternal Age
[y (SD)]/Nulliparity
[n (%)]
Controls: Mean
Maternal Age
[y (SD)]/Nulliparity
[n (%)]
Blood Sample
(Anticoagulant)/
Storage
Temperature(°C)
Gestational Age at
Sampling
(wk)
Control Group
[Mean (SD)
pg/mL]
Preeclamptic
Group
[Mean (SD) pg/mL]
Krauss
22
2004
(Germany/English)
44/177 Not stated/not stated Not stated/not stated Plasma (EDTA)/50°C 21–22 353
22–29 441 (median) PE HELLP: 286
(median); P.024
29–30 574
Tidwell
29
2001
(Taiwan/English)
14/25 Mild PE: 25.0 (3.7);
Severe PE: 25.5 (4.0)/
14 (100)
39.1 (2.0)/25 (100) Serum/70°C 5–15 58.55 (7.5) Mild PE: 25; P.01; sPE:
6; P.001
16–20 175.5 (21.64) Mild PE: 125; sPE: 32;
P.01
26–30 753.0 (65.7) Mild PE: 500; sPE: 100;
P.05
Bersinger
21
2004 (Norway-
Sweden/English)
28/65 29.6 (4.5)/Not stated 27.9 (4.0)/not stated Serum/70°C 17 600 500; P.031
25 1,500 800; P.005
33 1,800 700; P.006
Taylor
28
2003 (New Zeland/
English)
20/49 27.0 (6.6)/20 (100) 26.7 (4.5)/49 (100) Serum/80°C Less than 14 Less than 50 Less than 50
15–19 100 PE: 70; PESGA:40;
P.03
21–25 280 PE: 220; P.03PESGA:
155; P.001
27–30 640 PE: 300; P.001;
PESGA: 133; P0.001
35–38 250 PE: 100; P.001;
PESGA: 66; P.001
Tjoa
30
2001
(Netherlands/English)
18/44 34 (4)/5 (27.8) 34 (4)/14 (31.8) Plasma (heparin)/80°C 14–17 68.8 (28.2) 46.6 (31.3)
17–21 124.1 (39.8) 83.8 (12.3); P.007
Livingston
23
2001 22/22 Not stated/not stated Not stated/not stated Plasma (EDTA)/70°C 10–19 56.3 sPE: 98.8
35–40 449 sPE: 125.2; P.003
Thadhani
18
2004 (US/English) 40/80 31(6)/Not stated 30 (6)/not stated Serum/80°C 1st trimester 63 (145) 23 (24); P.05
Polliotti
26
2003 (US/English) 20/60 25.7 (4.9)/Not stated 27.2 (4.9)/not stated Serum/not stated 17 (2nd trimester) 122 (81) sPE: 61.3 (28.1); P.001
Parra
16
2005 (Chile/English) 33/137 29.8 (1.1)/17 (51.5) 30.6 (0.6)/37 (27) Plasma (Citrate,
EDTA)/84°C
11–14 45.7 (5.2) 42.5 (3.2)
22–25 400 210; P.05
Ong
25
2001(UK/English) 131/400 29.0 (5.6)/67(51.1) 28.2 (5.3)/197 (49.3) Serum/20°C 11–14 MoM 0.98 (0.51) MoM 1.09 (0.52)
Madazli
24
2005
(Turkey/English)
14/108 29.1 (4.5)/9 (64.3) 28.5 (5.1)/66 (61.1) Plasma (Heparin)/70°C 21–26 142.51 (30.82) 69.43 (27.31); P.001
Levine
13
2004 (US/English) 120/120 20.8 (4.5)/97 (80.8) 20.2 (3.6)/95 (79.2) Serum/70°C 13–16 142 90; P.01
17–20 280 190; P.01
21–32 700 634; P.01
33–41 600 388; P.02
Su
27
2001 (Taiwan/English) 27/227 32/not stated 29/not stated Serum/70°C 14 149
15 153
16 171
17 175
18 212
19 243
14–19 MoM: 1.00 MoM: 0.55; P.001
SD, standard deviation; EDTA, ethylenediaminetetraacetic acid; PE, preeclampsia; HELLP, hemolysis, elevated liver enzymes, low platelets; SGA, small for gestational age; Mild PE,
mild preeclampsia. sPE, severe preeclampsia; MoM, multiples of the median.
P values are from the comparison between preeclamptic and control groups.
172 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
significant for both groups during weeks 33– 41. Sim-
ilarly, in the other,
17
statistically significant levels were
present only in the severe preeclamptic group be-
tween weeks 25 and 34.5, whereas afterward both
subgroups showed significantly higher values than the
controls.
Likelihood ratios were reported only in two stud-
ies.
11,12
Levels of sFlt-1 higher than 1,575 pg/mL at 28
to 32 weeks gestation in the Chaiworapongsa et al
study
11
and higher than 957 pg/mL at 25 to 28 weeks
gestation in the Hertig et al study
12
were associated
with high level of prediction of preeclampsia (Table
3).
Interesting was the ability of sFlt-1 levels to
predict early preeclampsia (less than 37 weeks). One
study
13
reported that between gestational weeks 21
and 32, sFlt-1 levels within the highest quartile were
associated with early preeclampsia (odds ratio 5.1,
95% confidence interval 2.0 –13.0). Wathe´n and col-
leagues
19
reported that sFlt-1 concentrations decrease
by 15% from the first to the second trimester in
normal pregnancies, but this decrement did not occur
in women destined to develop preeclampsia.
Soluble fms-like tyrosine kinase-1 was always
measured with the same commercially available en-
zyme-linked immunosorbent assay (ELISA) kits
(R&D systems, Minneapolis, MN).
11–20
However, as-
say performance is affected by choice of serum or
plasma, collection procedure, processing, storage, and
preparation of the aliquot assayed. Plasma was ana-
lyzed in 3 of 10 studies,
11,15,16
but no authors provide
detailed information regarding sample collection and
handling procedures. In one,
16
either ethylenediami-
netetraacetic acid or citrate was used as anticoagulant,
although the latter seems not to have been validated
in this assay. Similarly, none of the five studies where
sFlt-1 was measured in serum
12,14,17,19,20
contained
descriptions of the procedures for sample collection.
The storing of multiple aliquots to avoid repeated
freeze-thawing was noted by only one group of au-
thors.
14
Another
18
stated that “samples were stored on
ice for less than 3 hours” before freezing, a step not
mentioned in the kit brochure.
In addition there are differences in assay proto-
cols among studies. Duplicate samples were assayed
in seven of the 10,
12–14,16,18,19,20
and a dilution step was
performed in two,
12,17
although the latter is not spec-
ified in the kit manufacturer’s instructions. Intra-assay
and interassay coefficients of variations were specified
in seven studies,
11,13–15,17–19
although in one,
17
only
interassay variability was noted. There were no dis-
cussions of the methods’ linearity range or how outlier
values were treated. Finally, the minimal detectable
concentration of serum or plasma reported by the
manufacturer of the assay is 5 pg/mL. Agreement
with this was noted in three reports,
13,14,19
whereas
higher levels were cited in two,
11,15
one reporting a
minimal detectable level of 80 pg/mL.
15
No informa-
tion on minimal levels of detection was provided in
four reports.
12,16–18
In 14 of 319 studies placental growth factor levels
were measured at different gestational ages in women
destined to develop preeclampsia (preeclamptic
group) and in normotensive gestations (control
group)
13,16,18,21–31
(Table 2). Only 2 were prospec-
tive.
24,29
Placental growth factor levels were measured
in blood samples in 13 of 14 of the studies
13,16,18,21–30
and in urine the other
31
(the study population in this
study is the same as the one included in Levine et
al
13
). Sensitivity and specificity analysis appears in
only 6 of 14 reports.
13,18,24,26,27,29
According to likeli-
hood ratios, the predictive ability of placental growth
factor measured in blood before gestational week 25
was moderate
24,27,29
(Table 4).
Table 3. Predictive Ability of Soluble fms-Like Tyrosine Kinase-1 for Preeclampsia
Study
Gestational
Week
Cutoff
Points for
sFlt-1
(pg/mL) Sensitivity Specificity
Odds Ratio
(95% CI)
Likelihood
Ratio of a
Positive
Test
Chaiworapongsa
11
2005 24.1–28 1,560 16.7 97.4 6.4
28.1–32 1,575 83 95 16.6
28.1–32 1,575 18.5 95 3.7
32.1–37 2,164 70 97 23.3
Hertig
12
2004 25–28 957 80 100 Infinity
Levine
13
2004 21–32 More than1,131 5.1 (2.0–13.0)
33–41 More than 2,191 6.0 (2.9–12.5)
Wathe´n
19
12–15 More than 575 3.5 (0.9–13.5)
16–20 More than 517 11.6 (1.2–109.2)
sFlT-1, soluble fms-like tyrosine kinase-1; CI, confidence interval.
VOL. 109, NO. 1, JANUARY 2007 Widmer et al Mapping the Theories of Preeclampsia 173
Placental growth factor was measured in blood
before week 15 in eight reports
13,16,18,23,25,28–30
(Fig.
5A). Ong et al
25
reported the results as median
multiple of the median only (not included in Fig. 6),
but it is considered in this evaluation. Levels were
significantly lower in women destined to develop
preeclampsia compared with those who remained
normotensive in only three of eight studies;
13,18,29
no
differences were present in the other five re-
ports.
16,23,25,28,30
Four of the latter five studies reported
a decrease of placental growth factor levels in the
preeclamptic group, whereas one
23
noted increased
levels in preeclamptic women (Fig. 5B).
Placental growth factor data during the 15-25
weeks gestational window were presented in nine
reports
13,16,21,24,26,27–30
(Fig. 6A-B). In one, results are
only presented as the median multiple of the medi-
an,
27
considered in the analysis but not included in
Figure 6A. Six of nine reports showed statistically
significantly lower values in the preeclamptic group
as compared with the control group.
13,16,21,24,27,30
Tay-
lor and colleagues
28
also noted lower levels of circu-
lating placental growth factor in the preeclamptic
group but this difference became statistically signifi-
cant only after gestational week 20. Of interest, levels
were significantly lower before gestational week 21 in
the preeclamptics who delivered small for gestational
age babies.
28
In one study
26
including only severe
disease, the differences were statistically significant,
whereas in another,
29
results in the whole preeclamp-
tic group were similar to controls but significantly
different when severe preeclamptics were analyzed.
Fig. 2. A. Soluble fms-like tyrosine
kinase-1 mean levels before gesta-
tional week 15. In the X axis are
individual reports, study’s first au-
thor and gestational week at blood
sampling. B. Differences in mean
soluble fms-like tyrosine kinase-1
levels before gestational week 15.
sFlt-1, soluble fms-like tyrosine ki-
nase-1.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
174 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
Placental growth factor levels measured after
gestational week 25 were statistically significantly
lower in women developing preeclampsia in each of
the six studies reviewed
13,21,22,23,28,29
(Fig. 7A-B), but in
two reports
23,29
significant differences were detected
only in severe preeclampsia. Yet, in one study
22
that
considered both preeclampsia and hemolysis, ele-
vated liver enzymes, low platelets, the sensitivity and
specificity were low, leading the authors to conclude
that placental growth factor during the second half of
the pregnancy has limited predictive value.
22
We could locate but one study meeting inclusion
criteria where placental growth factor was measured
in urine.
31
It showed that levels in control women
increased during the first two trimesters, reaching a
peak at 29 –32 weeks and decreasing thereafter.
Women who subsequently developed preeclampsia
followed a similar pattern early in pregnancy, but
urinary placental growth factor levels were signifi-
cantly lower after 25 weeks.
A positive factor in laboratory methodological
quality of the included studies is that placental growth
factor was measured with the same commercially
available ELISA kits (R&D systems) in all 14 stud-
ies.
13,16,18,21–31
None includes details relating to collec-
tion, storage, and dilution procedures for very high
values. In the study that measured placental growth
factor in urine, the ELISA assay kits were validated
for use in urine specimens, because the R&D systems
kits have been developed and tested specifically for
the assessment of placental growth factor in serum
and plasma but not in urine. Important information
on urinary sample handling and processing was not
provided.
In six of 14 reports,
13,18,27–30
the text implies that
the authors did not test the intraday and interday
Fig. 3. A. Mean soluble fms-like
tyrosine kinase-1levels during ges-
tational weeks 15–25. In the X axis
are individual reports, study’s first
author, and gestational week at
blood sampling. B. Differences in
mean soluble fms-like tyrosine ki-
nase-1levels during gestational
weeks 15–25. sFlt-1, soluble fms-
like tyrosine kinase-1.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
VOL. 109, NO. 1, JANUARY 2007 Widmer et al Mapping the Theories of Preeclampsia 175
imprecision (expressed as coefficient of variation) but
reported values supplied by the assay kit vendor. We
consider this highly inappropriate for studies de-
signed to provide information that may affect prac-
tice. Similarly, two reports,
27,29
cited a minimal detect-
able dose for placental growth factor of 7 pg/mL, the
value reported in the kit brochure. Range of linearity
was reported in a single study.
21
Fig. 4. A. Mean soluble fms-like
tyrosine kinase-1 levels after ges-
tational week 25. In the X axis
are individual reports, study’s
first author, and gestational week
at blood sampling. B. Differ-
ences in mean soluble fms-like
tyrosine kinase-1 levels after ges-
tational week 25. sFlt-1, soluble
fms-like tyrosine kinase-1.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
Table 4. Predictive Ability of Placental Growth Factor for Preeclampsia
Study
Gestational
Week
Cutoff Point
of PlGF
(pg/mL) Sensitivity Specificity
Odds Ratio or
Relative Risk
(95% CI) ROC Area
Likelihood
Ratio of a
Positive Test
Leviner
13
2004 13–20 Less than 87 6.7 (1.6–27.5)
21–32 Less than 363 1.2 (0.5–3.1)
Madazli
24
2005 21–26 Less than 90 92.9 94.4 16.6
100 88.1
Poliotti
26
2003 17 Less than 80.8 4.2 (1.35–13.6) 0.799
Su
27
2001 14–19 MoM0.55 70 70 2.5 fold per 0.1MoM 0.79 2.3
Thadani
18
2004 10 Less than 12 14.7 (2.0–102.2) 0.69
Tidwell
29
2001 5–15 Less than 32 90.9 90.5 95 (7.6–1,180) 9.6
16–20 Less than 90 66.7 88.7 16 (2.4–106) 5.9
PlGF, placental growth factor; CI, confidence interval; ROC, receiver operating characteristic; MoM, multiples of median.
176 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
An area of concern is the large variation in the
values reported for the control groups across studies
within the same gestational age window. Differences
within the control groups’ mean values among studies
are larger than those between controls and pre-
eclamptic women. This is likely due to the heteroge-
neity in sample handling, processing, and laboratory
procedures rather than a biologic effect.
CONCLUSION
The aim of this systematic review was to evaluate the
evidence of the association between angiogenic (pla-
cental growth factor) and antiangiogenic (sFlt-1) pro-
tein levels before the clinical presentation of pre-
eclampsia for their eventual use in the prediction of
the condition. The latter did not seem to be the case
for samples obtained during the first and early second
trimesters. There were, however, significant differ-
ences in levels of placental growth factor or sFlt-1
after gestational week 25 between women with nor-
mal pregnancies and those destined to develop severe
preeclampsia, implying a relationship with the patho-
physiology of the disease rather than its cause.
There is considerable heterogeneity among re-
ports. Several reasons could account for this: 1) There
are differences in the anylate and storage conditions.
According to good clinical practice, laboratories
should directly assess imprecision, inaccuracy, linear-
ity, and minimal detectable dose for each assay, and
the performance of the assay should be confirmed
using internal and external quality controls. The
implementation of these recommendations might sig-
nificantly reduce the heterogeneity of the results. 2)
There are differences in the gestational periods se-
lected for blood sampling; although we arbitrarily
grouped studies into three gestational windows, ges-
Fig. 5. A. Mean placental growth
factor levels before gestational
week 15. In the X axis are individ-
ual reports, study’s first author,
and gestational week at blood
sampling. B. Differences in mean
placental growth factor levels be-
fore gestational week 15. sFlt-1,
soluble fms-like tyrosine kinase-1.
PlGF, placental growth factor.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
VOL. 109, NO. 1, JANUARY 2007 Widmer et al Mapping the Theories of Preeclampsia 177
tational age at sampling still varied considerably in
the studies within each group. 3) There are different
inclusion and exclusion criteria. Some reports include
women with risk factors for preeclampsia, whereas
others excluded this group; in some the study popu-
lation was exclusively nulliparous women, whereas all
parities were included in others. The parity issue is of
particular significance because circulating sFlt-1 levels
have been shown to be higher in first compared with
second pregnancies in the same women,
18,32
as is their
risk of developing preeclampsia. 4) There are differ-
ences in reporting the results. Some studies evaluated
sFlt-1 or placental growth factor levels in women
destined to have mild preeclampsia separately from
gravidas later developing severe disease, whereas
others did not make this distinction, reporting mild
and severe disease as a single group. The need for
such specificities limits the potential use in practice.
Finally, the large variation of values among the con-
trol groups is of concern for eventually selecting a
cutoff point for screening.
The evidence presented supports the possibility
that these two markers are associated with the
pathophysiology of preeclampsia or its phenotypes,
especially data from samples obtained after gesta-
tional week 25 from women whose disease will be
severe. However, it is not clear if such association is
part of the causal path (temporal association) or is
just an expression of its pathophysiologic alter-
ations. We believe that the evidence is neither
strong enough nor sufficient to recommend placen-
tal growth factor and sFlt-1 to screen women at risk
to develop preeclampsia, even after gestational
week 25. Prospective studies employing rigorous
laboratory and study design criteria are needed to
determine the clinical usefulness of these tests. It
Fig. 6. A. Mean placental growth
factor mean levels during gesta-
tional weeks 15–25. In the X axis
are individual reports, study’s first
author and gestational week at
blood sampling. B. Differences in
mean placental growth factor lev-
els during gestational weeks 15–
25. sFlt-1, soluble fms-like ty-
rosine kinase-1. PlGF, placental
growth factor.
Widmer. Mapping the Theories of
Preeclampsia. Obstet Gynecol 2007.
178 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
has been recently reported that a novel soluble
form of endoglin (sEng) could act in concert with
sFlt-1 to amplify endothelial dysfunction and in-
duce clinical signs of severe preeclampsia.
33
It is
possible that if used in conjunction with the mark-
ers reviewed here could improve their predictive
performance. The data in this review have been
used by us to design a study within the WHO
Global Program to Conquer Preeclampsia sched-
uled to start mid 2006; in this investigation approx-
imately 10,000 women will be screened serially to
evaluate these biomarkers for preeclampsia.
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180 Widmer et al Mapping the Theories of Preeclampsia OBSTETRICS & GYNECOLOGY
    • "The results from these experiment correlate with the findings shown in cells in where the treated group developed PE-like symptoms, significant hypertension and heavy albuminuria and downregulation of PlGF (Maynard et al., 2003). Despite all these recent findings the genesis of ED in PE still an enigma (Nagamatsu et al., 2004; Widmer et al., 2007). However, recently, another interesting study explored the effects of hypoxia on the regulation of VEGF, PlGF, and sFlt-1, in isolated cytotrophoblasts , HUVECs and villous fibroblasts. "
    [Show abstract] [Hide abstract] ABSTRACT: Preeclampsia (PE) is an often fatal pathology characterized by hypertension and proteinuria at the 20th week of gestation that affects 5-10% of the pregnancies. The problem is particularly important in developing countries in where the incidence of hypertensive disorders of pregnancy is higher and maternal mortality rates are 20 times higher than those reported in developed countries. Risk factors for the development of PE include obesity, insulin resistance and hyperlipidemia that stimulate inflammatory cytokine release and oxidative stress leading to endothelial dysfunction (ED). However, how all these clinical manifestations concur to develop PE is still not very well understood. The related poor trophoblast invasion and uteroplacental artery remodeling described in PE, increases reactive oxygen species (ROS), hypoxia and ED. Here we aim to review current literature from research showing the interplay between oxidative stress, ED and PE to the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.
    Full-text · Article · Oct 2014
    • "Preeclampsia remains one of the major causes of maternal and neonatal morbidity worldwide, affecting up to 5–8% of pregnant women (Turner, 2010). Preeclampsia is considered a " disease of theories " , in which a wide spectrum of explanations has been put forward, proposing a range of molecular and environmental causes (Widmer et al., 2007; Mignini et al., 2006). It is characterized by an abnormal vascular response to placentation that is associated with endothelial cell dysfunction and systemic vascular resistance (Robillard et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Preeclampsia involves an exacerbated maternal inflammatory response that suggests a possible role of innate immunity. NK cells can promote this kind of response through cytokine production and the expression of activating or inhibitory receptors. The aims of the present study were to explore cytokine production by peripheral blood mononuclear cells, as well as cytotoxic ability and receptor expression for HLA-E and HLA-G molecules in peripheral natural killer (NK) cells of women with early-onset severe preeclampsia without HELLP (hemolysis, elevated liver enzyme levels and a low platelet count) syndrome. The expression of the ILT2, KIRDL4, NKG2A, and NKG2C receptors and of cytotoxic activity was measured in non-stimulated NK cells, whereas the intracellular expression of IL-4, IL-10, IL-13, IL-12, IFNγ, TNF and VEGF, was assessed in non-stimulated peripheral blood mononuclear cells subsets using flow cytometry. Circulating soluble HLA-G was also determined by ELISA. The intracellular cytokines tested were significantly higher in NK cell subsets from severely preeclamptic women compared with the control group. On the other hand, the percentage of NK cells expressing NKG2A or NKG2C and the cytotoxic activity of NK cells were significantly higher in severely preeclamptic women. Furthermore, there was a significant correlation between urine protein concentration and soluble human leukocyte antigen G (soluble HLA-G) in serum. We conclude that patients with early-onset severe preeclampsia without HELLP syndrome have increased NK cell function related to cytokine production, cytotoxicity and expression of lectin-like receptors such as NKG2.
    Full-text · Article · Feb 2013
    • "The angiogenic growth factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are important for placental development and angiogenesis, whereas soluble fms-like tyrosine kinase 1 (sFlt-1) binds to these proteins and thereby inhibits their activity. Previous studies have demonstrated elevated blood sFlt-1 levels or reduced blood PlGF levels in women whose pregnancies were complicated by intrauterine growth restriction, preeclampsia, and gestational hypertension (Asvold et al. 2011; Levine et al. 2004; Smith et al. 2007; Thadhani et al. 2004), and in infants of mothers with preeclampsia (Catarino et al. 2009; Staff et al. 2005); but other studies reported no associations or associations in the opposite direction (Asvold et al. 2011; Jacobs et al. 2011; Smith et al. 2007; Thadhani et al. 2004; Widmer et al. 2007). In addition, indices of placental vascular resistance and the presence of uterine artery notching (an abnormality of the Doppler ultrasound waveform that indicates increased blood flow resistance) have been used to identify complicated pregnancies (Cnossen et al. 2008; Schlembach et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (–11.8 g; 95% CI: –20.9, –2.7, and –10.7 g; 95% CI: –19.0, –2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences.
    Full-text · Article · Aug 2012
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